Warfarin – the anticoagulant that dances on the wire “Coagulation” may not always be as good as resin into amber or water droplets into snowflakes. Sometimes, it can come at an inopportune time, such as when blood clots in the blood vessels. Therefore, we need drugs to fight against it, that is, anticoagulants. Warfarin is an important member of the anticoagulants. It does not have an illustrious origin, but it has excellent efficacy and has endured for a long time. It is both convenient and cumbersome to take, and the dose must be taken with care, like dancing on a tightrope. There are many interesting stories about it. A strange phenomenon is gradually spreading in many pastures in Canada and the northern United States. Cattle and sheep have suddenly become so vulnerable that their blood does not clot properly after bleeding wounds, and operations that normally do not seem life-threatening enough, such as castration or dehorning, this time leave them bleeding to death. Strangely enough, the livestock living conditions and the feed they ate were not different from previous years, which left the ranchers puzzled. To uncover the culprit of the bizarre incident, Canadian veterinary pathologist Frank? Schofield (Frank Schofield) investigated this. He found that during the year, the weather was unusually warm, so that the farm’s stored forage (leguminous herbaceous rhizome, commonly known as wild clover) mold and rot, so it is presumed that these moldy forage caused clotting disorders in livestock. Schofield confirmed his suspicions by feeding fresh and moldy forage to rabbits, resulting in abnormal bleeding in the rabbits that ate the moldy forage, while the rabbits that ate the fresh forage were unharmed. Chemist Karl? Paul? Link (Karl Paul Link) finally isolated the anticoagulant substance from the moldy grass and determined its structure. This is a bicoumarin-like substance, which consists of two molecules of coumarin-like substances combined. Coumarins are very common in plants and are responsible for the sweet aroma of the herb rhinoceros (which is why it is called “Sweet Clover”, a plant that actually tastes bitter). The single coumarin molecule itself does not cause a clotting disorder, but this effect occurs when two molecules combine to form a double coumarin structure (which is what happens when the grass is moldy). In the years since, several substances with similar molecular structures have been discovered. Not surprisingly, they all had an anticoagulant effect. In the first years after the discovery of this substance, people did not think of using it as a drug, but rather to make it into rat poison. This was probably because the tragic deaths of cattle and sheep in the pasture had left the impression that “bicoumarin = poison”. In order to make the rat poison more powerful, Link made structural modifications to bicoumarin and obtained a more potent anticoagulant substance in 1948, and named it warfarin. The main character of this article is now officially on the scene. For several years thereafter, warfarin was used as a rat poison. Rats are wary by nature, and once they find out that their kind has eaten something and died immediately, other rats will not touch this food, which makes how to make the rat drug effective in the long run has become a problem. However, it is said that rats do not die immediately after eating warfarin, making it difficult for their forgetful counterparts to link warfarin directly to the death of their brethren, so the rat poison can remain effective for a longer period of time. As a result, warfarin was a popular rat poison for a long time, and is still used today. Rat poison is always associated with suicide, and warfarin was no exception when a disillusioned American soldier attempted suicide by consuming warfarin in 1951. Whether it was his luck or misfortune, the man was taken to the hospital and made a full recovery after being treated with vitamin K (which counteracts the effects of warfarin, as will be mentioned below). This accident led to the discovery that this rat poison was unexpectedly safe to use on people. And it is true that many patients need anticoagulant substances to prevent thrombosis in clinical practice. In 1954, warfarin was officially approved for use in humans. Since then, a new chapter in the history of anticoagulant drugs has been opened. Oral anticoagulation, unique Coagulation is a very complex process, and memorizing all of this process has deeply troubled many students of physiology …… The process consists of a series of interlocking reactions, which is often visualized as a “coagulation waterfall. The key to coagulation is the activation of thrombin, which then allows the fibrin clot to form. Activation of thrombin requires the cooperation of several coagulation factors. Of the many coagulation factors, a significant portion requires the involvement of vitamin K for their formation and activation. Vitamin K needs to be continuously recycled in the body with the help of vitamin K epoxide reductase, and warfarin can impede this cycle by preempting vitamin K epoxide reductase. As a result, the vitamin K-dependent clotting factors lose their “backbone” and their amount and activity are greatly reduced, making the blood less likely to clot. The clinical importance of warfarin can be considered irreplaceable. Many patients are prone to abnormal blood clotting, or thrombosis, in their blood vessels as a result of their disease. Not only can the clot block the blood vessel in place and interfere with the blood supply, it can also dislodge and then embolize elsewhere along the bloodstream – either of which can be dangerous, especially if it occurs in a very important organ like the heart, brain, or lungs. That’s when anticoagulant drugs are needed to help prevent blood clots. Prior to the introduction of warfarin, the anticoagulant drug in clinical use was heparin (an anticoagulant that was already in the body and is still in use today), which could only be injected and was inconvenient for patients who needed it for long periods of time. The advent of warfarin solved this problem, and it was clearly much more acceptable to take a few pills than to receive daily injections. Moreover, no new oral anticoagulants have been available for decades after warfarin was introduced, which has made it durable. Although in recent years there have been some new oral anticoagulants that are more convenient to use, such as rivaroxaban and dabigatran, which may gradually take the place of warfarin in the future. However, for the time being, warfarin is cheap and has a lot of experience in clinical use, and will remain the mainstream for a number of years to come. Balance on steel wire There is no doubt that warfarin is a very effective drug, just a few milligrams is enough to prevent the formation of blood clots. But it can also cause some trouble. Warfarin has a narrow therapeutic window, and a smaller dose will not achieve the desired effect, while a larger dose will increase the risk of bleeding. Bleeding is the most common side effect of warfarin, and it is also a very dangerous side effect that can be as life-threatening as a blood clot. This makes warfarin treatment like walking a tightrope, and one must be careful to maintain a balance in order to reach the treatment goal safely. Even more problematic is that the conditions of this balance are not static. The efficacy of warfarin can waver depending on many factors. A gravity-sensitive game called “Wire Hero” is probably the most apt illustration of this effect. In the game, the player controls a tightrope walking clown to the other end of the wire to the end. In the wire to maintain balance itself is not easy, more damaging is the way will encounter many disturbances, such as a bird resting on the balance bar, or a sudden gust of wind, then you have to quickly adjust to establish a new balance. First of all, the intake of vitamin K is a problem. Vitamin K can diminish or even completely counteract the effects of warfarin, and some foods are rich in vitamin K, such as spinach (90 grams of cooked spinach contains 444.2 micrograms of vitamin K, 555% of the average person’s daily requirement) and kale (67 grams of raw kale contains 547.4 micrograms of vitamin K, 684% of the daily requirement). If you eat too much of such food, warfarin will not work naturally. In addition to this, the effectiveness of warfarin is affected by many drugs. Many drugs in the body are metabolized by the liver into inactive metabolites before being excreted, as is the case with warfarin. Drug metabolizing enzymes are not “one-to-one” and many drugs share the same enzymes with warfarin. When they coexist with warfarin in the body, they compete with warfarin for metabolizing enzymes, resulting in slower metabolism of warfarin and higher drug concentrations. There are also drugs that can increase the synthesis and activity of metabolizing enzymes, which in turn can reduce the concentration and efficacy of warfarin. The number of these drugs that can affect the efficacy of warfarin is quite impressive, and includes some herbs (e.g. ginseng can reduce the effect of warfarin). In addition to this, genetic differences between people should not be underestimated. In recent years, the phenomenon of genetic differences causing differences in efficacy has become better known and a new discipline, pharmacogenetics, has been developed as a result. The genes that can affect the efficacy of warfarin are mainly genes encoding its target enzymes and genes for drug metabolizing enzymes, both of which have various alleles of varying activity, and people carrying different alleles have quite different sensitivity to warfarin and require different doses. In the face of these and other countless factors, taking them all into account is enough to give doctors and pharmacists a long headache. Fortunately, we have a “no change, no change” solution – monitor the efficacy and adjust the dose. The efficacy of warfarin can be directly reflected by the coagulation function, which is relatively simple to test with a blood draw. All that is needed is to start treatment with a smaller dose and then monitor the coagulation function frequently, adjusting it according to the results so that the results eventually plateau. However, even after the results have plateaued, regular monitoring is still required. Such monitoring is indeed somewhat cumbersome and compromises the convenience of warfarin as an oral medication. But with its escort, warfarin is able to dance on the wire and become a long-lasting anticoagulant drug.